We have studied the clinical manifestations of cerebrovascular dysfunction caused by traumatic brain injury (TBI) during the past grant period. In patients, we observed a wide spectrum of cerebrovascular pathology, ranging from impaired pressure autoregulation which causes TBI patients to be more vulnerable to secondary ischemic insults, to severe global cerebral ischemia. The level of cerebral blood flow (CBF), especially within the first 12hr after injury, is strongly predictive of neurological outcome with each 10ml/100g/min increase in average cortical CBF resulting in a 3-fold increase in the chances of surviving to hospital discharge. In an experimental model of TBI, we have demonstrated that the hypoperfusion and dysfunction of blood flow regulation is caused at least in part by depletion of the nitric oxide (NO) produced by the endothelial isoform of NOS. We have also found that with the relative deficiency of NO, endothelium-derived hyperpolarizing factor (EDHF) becomes upregulated and may be an important endogenous mechanism for maintaining cerebral perfusion after TBI. The overall hypothesis of this proposal is that TBI causes a reduction in CBF in the early post-injury period that contributes to the brain damage by 2 mechanisms: 1-if the reduction in CBF is severe enough and lasts long enough, primary ischemic injury occurs 2-if the reduction in CBF is more modest, primary ischemic injury may not occur, but the brain is more susceptible to secondary ischemic insults. Trauma is the most common cause of death in the 1-44 yr age group, and the third most common cause for the entire US population. Trauma accounts for more loss of work life-years than cancer and cardiovascular diseases combined. Effective treatments for this important public health disorder are needed. Treatment of the cerebrovascular dysfunction caused by TBI could significantly improve neurological recovery following trauma. We will approach this problem with a combination of laboratory and clinical studies, each addressing some aspect of vascular dysfunction. The components of this proposal include three cores and the following four projects: Project 1. Effect of Erythropoietin on Vascular Dysfunction in Human TBI Project 2. Effect of Erythropoietin on Anemia and Need for Transfusion Project 3. EDHF Following Traumatic Brain Injury Project 4. Neuroprotection of Erythropoietin Signaling in TBI